Carbamate and oxamide compounds Number:6,743,788 from the United States Patent and Trademark Office (PTO) owispatent Disclosed are novel aromatic compounds of the formula(I) described herein, wherein G, E, W, Ar, X, Y and Z are disclosed herein. The compounds are useful for treating cytokine mediated diseases or conditions such as chronic inflammatory diseases. Also disclosed are pharmaceutical compositions containing and processes of making such compounds. ##STR1##<H compounds, Carbamate, Carbamate, and, o, 6743788.html, Patent, pto, 6743788

Title: Carbamate and oxamide compounds

Abstract: Disclosed are novel aromatic compounds of the formula(I) described herein, wherein G, E, W, Ar, X, Y and Z are disclosed herein. The compounds are useful for treating cytokine mediated diseases or conditions such as chronic inflammatory diseases. Also disclosed are pharmaceutical compositions containing and processes of making such compounds. ##STR1##

Patent Number: 6,743,788 Issued on 06/01/2004 to Cirillo, et al.

Inventors: Cirillo; Pier Francesco (Woodbury, CT), Kamhi; Victor (Danbury, CT), Regan; John Robinson (Larchmont, NY), Tsang; Michele (Calgary, CA)
Assignee: Boehringer Ingelheim Pharmaceuticals, Inc. (Ridgefield, CT)

Appl. No.: 10/147,675

Filed: May 17, 2002

Current U.S. Class: 514/217.05 ; 514/227.8; 514/231.8; 514/232.2; 514/235.5; 514/235.8; 514/237.2; 514/239.5; 540/598; 544/121; 544/122; 544/124; 544/128; 544/129; 544/135; 544/139; 544/143; 544/146; 544/149; 544/153; 544/160; 544/165; 544/60; 544/62

Current International Class: C07C 275/40 (20060101); C07C 275/00 (20060101); C07D 207/00 (20060101); C07D 295/185 (20060101); C07D 207/08 (20060101); C07D 295/192 (20060101); C07D 405/00 (20060101); C07D 401/00 (20060101); C07D 295/135 (20060101); C07D 295/00 (20060101); C07D 401/12 (20060101); C07D 239/00 (20060101); C07D 239/26 (20060101); C07D 405/12 (20060101); C07D 241/00 (20060101); C07D 307/00 (20060101); C07D 213/00 (20060101); C07D 241/24 (20060101); C07D 239/28 (20060101); C07D 213/38 (20060101); C07D 307/12 (20060101); C07D 413/12 (20060101); C07D 413/00 (20060101)

Field of Search: 544/121,122,128,129,124,135,137,139,143,160,165,166,153,149,62,60 540/598 514/217.05,227.8,231.8,232.2,235.5,235.8,236.5,236.6,237.2,239.5

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6211373	April 2001	Widdowson et al.
6262113	July 2001	Widdowson et al.
6297381	October 2001	Cirillo et al.
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6329415	December 2001	Cirillo et al.
6333325	December 2001	Cirillo et al.
6358945	March 2002	Cirillo et al.

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International Search Report..

Primary Examiner: Berch; Mark L.
Assistant Examiner: Habte; Kahsay
Attorney, Agent or Firm: Raymond; Robert P. Bottino; Anthony P. Witkowski; Timothy X.

Parent Case Text

RELATED APPLICATION DATA

This application claims benefit to U.S. provisional application No. 60/293,600 filed May 25, 2001.

Claims

What is claimed is:

1. A compound of the formula (I): ##STR81## wherein: E is is a group chosen from --O--, --NH-- and --S--; G is: phenyl, naphthyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl; pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzooxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dibenzofuranyl, dihydrobenzothiophenyl, benzooxazolonyl, benzo[1,4]oxazin-3-onyl, benzodioxolyl, benzo[1,3]dioxol-2-onyl, benzofuran-3-onyl, tetrahydrobenzopyranyl, indolyl, 2,3-dihydro-1H-indolyl, indolinyl, indolonyl, indolinonyl, phthalimidyl, chromoyl; oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholino, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxidyl, oxazolinyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, thiazolinyl, imidazolinyl, tertrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomorpholino, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or dithianyl; wherein G is substituted by one R.sub.3 and further substituted by one or more R.sub.1 or R.sub.2 ; Ar is: phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl, benzofuranyl, dihydrobenzofuranyl, indolinyl, benzothienyl, dihydrobenzothienyl, indanyl, indenyl or indolyl each being optionally substituted by one or more R.sub.4 or R.sub.5 ; X is: a C.sub.5-8 cycloalkyl or cycloalkenyl optionally substituted with one to two oxo groups or one to three C.sub.1-4 alkyl, C.sub.1-4 alkoxy or C.sub.1-4 alkylamino chains each being branched or unbranched; aryl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperidinyl, benzimidazole, 3H-imidazo[4,5-b]pyridine, piperazinyl, pyridazinyl or pyrazinyl; each being optionally independently substituted with one to three C.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, nitrile, amino, mono- or di-(C.sub.1-3 alkyl)amino, mono- or di-(C.sub.1-3 alkylamino)carbonyl, NH.sub.2 C(O), C.sub.1-6 alkyl-S(O).sub.m or halogen; Y is: a bond or a C.sub.1-10 saturated or unsaturated branched or unbranched carbon chain, wherein one or more C atoms are optionally replaced by O, N, or S(O).sub.m ; and wherein Y is optionally partially or fully halogenated and optionally independently substituted with one to two oxo groups, nitrile, amino, imino, phenyl or one or more C.sub.1-4 alkyl optionally substituted by one or more halogen atoms; Z is: morpholinyl, optionally substituted with one to three halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-3 alkoxy-C.sub.1-3 alkyl, C.sub.1-6 alkoxycarbonyl, aroyl, C.sub.1-3 acyl, oxo, hydroxy, pyridinyl-C.sub.1-3 alkyl, imidazolyl-C.sub.1-3 alkyl, tetrahydrofuranyl-C.sub.1-3 alkyl, nitrile-C.sub.1-3 alkyl, nitrile, carboxy, phenyl wherein the phenyl ring is optionally substituted with one to two halogen, C.sub.1-6 alkoxy, hydroxy or mono- or di-(C.sub.1-3 alkyl)amino, C.sub.1-6 alkyl-S(O).sub.m, or phenyl-S(O).sub.m wherein the phenyl ring is optionally substituted with one to two halogen, C.sub.1-6 alkoxy, hydroxy, halogen or mono- or di-(C.sub.1-3 alkyl)amino; or Z is optionally substituted with one to three amino or amino-C.sub.1-3 alkyl wherein the N atom is optionally independently mono- or di-substituted by aminoC.sub.1-6 alkyl, C.sub.1-3 alkyl, arylC.sub.0-3 alkyl, C.sub.1-5 alkoxyC.sub.1-3 alkyl, C.sub.1-5 alkoxy, aroyl, C.sub.1-3 acyl, C.sub.1-3 alkyl-S(O).sub.m -- or arylC.sub.0-3 alkyl-S(O).sub.m -- each of the aforementioned alkyl and aryl attached to the amino group is optionally substituted with one to two halogen, C.sub.1-6 alkyl or C.sub.1-6 alkoxy; or Z is optionally substituted with one to three aryl, heterocycle or heteroaryl as hereinabove described in this paragraph each in turn is optionally substituted by halogen, C.sub.1-6 alkyl or C.sub.1-6 alkoxy; each R.sub.1 is independently: C.sub.1-10 alkyl branched or unbranched optionally partially or fully halogenated, wherein one or more C atoms are optionally independently replaced by O, N or S(O).sub.m, and wherein said C.sub.1-10 alkyl is optionally substituted with one to three C.sub.3-10 cycloalkyl, hydroxy, oxo, phenyl, naphthyl, or R.sub.1 is cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, or cycloheptyloxy each being optionally partially or fully halogenated and optionally substituted with one to three C.sub.1-3 alkyl groups optionally partially or fully halogenated, nitrile, hydroxyC.sub.1-3 alkyl or aryl; phenyloxy or benzyloxy each being optionally partially or fully halogenated and optionally substituted with one to three C.sub.1-3 alkyl groups optionally partially or fully halogenated, nitrile, hydroxyC.sub.1-3 alkyl or aryl; cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each being optionally partially or fully halogenated and optionally substituted with one to three C.sub.1-3 alkyl optionally partially or fully halogenated, nitrile, hydroxyC.sub.1-3 alkyl or aryl; C.sub.3-10 branched or unbranced alkenyl each being optionally partially or fully halogenated, and optionally substituted with one to three C.sub.1-5 branched or unbranched alkyl, phenyl, naphthyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, wherein such cycloalkenyl group is optionally substituted with one to three C.sub.1-3 alkyl groups; oxo, nitrile, halogen; or C.sub.3-6 alkynyl branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, NH or S(O).sub.m and wherein said alkynyl group is optionally independently substituted with one to two oxo groups, hydroxy, pyrroldinyl, pyrrolyl, tetrahydropyranyl, one or more C.sub.1-4 alkyl optionally substituted by one or more halogen atoms, nitrile, morpholinyl, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono- or di(C.sub.1-3 alkyl)amino optionally substituted by one or more halogen atoms; each R.sub.2, R.sub.4, and R.sub.5 is a C.sub.1-6 branched or unbranched alkyl optionally partially or fully halogenated, C.sub.1-6 acyl, aroyl, C.sub.1-4 branched or unbranched alkoxy, each being optionally partially or fully halogenated, halogen, methoxycarbonyl, C.sub.1-4 alkyl-S(O).sub.m branched or unbranched and optionally partially or fully halogenated, or phenyl-S(O).sub.m ; R.sub.3 which is covalently attached to G, is ##STR82## wherein for R.sub.3 : R.sub.a and R.sub.b are each independently: hydrogen, a C.sub.1-10 saturated or unsaturated branched or unbranched carbon chain, wherein one of the C atoms is optionally replaced by O or N and optionally substituted by oxo; or R.sub.a and R.sub.b are each independently C.sub.3-7 cycloalkylC.sub.0-6 alkyl, phenylC.sub.0-6 alkyl, heterocycleC.sub.0-6 alkyl or heteroarylC.sub.0-6 alkyl wherein the C.sub.0-6 alkyl portion for each is optionally substituted by oxo and wherein the heterocycle or heteroaryl moiety is chosen from morpholinyl, pyridinyl, piperidinyl, piperazinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxazoyl,[1,3,4]oxadiazol, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, quinoxalinyl, quinazolinyl and indazolyl, each C.sub.3-7 cycloalkyl, phenyl, heterocycle or heteroaryl is optionally substituted by C.sub.1-6 alkyl, halogen, hydroxy, carboxy, oxo, amino, imino, nitro or nitrile; or R.sub.a and R.sub.b together with the nitrogen atom to which they are attached form a morpholino, pyridinyl, piperidinyl, piperazinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxazoyl, [1,3,4]oxadiazol, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, cinnolinyl, pterindinyl, phthalazinyl, naphthypyridinyl, quinoxalinyl, quinazolinyl, purinyl or indazolyl, or a fused heteroaryl selected from cyclopentenopyridinyl, cyclohexanopyridinyl, cyclopentanopyrimidinyl, cyclohexanopyrimidinyl, cyclopentanopyrazinyl, cyclohexanopyrazinyl, cyclopentanopyridazinyl, cyclohexanopyridazinyl, cyclopentanoquinolinyl, cyclohexanoquinolinyl, cyclopentanoisoquinolinyl, cyclohexanoisoquinolinyl, cyclopentanoindolyl, cyclohexanoindolyl, cyclopentanobenzimidazolyl, cyclohexanobenzimidazolyl, cyclopentanobenzoxazolyl, cyclohexanobenzoxazolyl, cyclopentanoimidazolyl and cyclohexanoimidazolyl, wherein each of the above is optionally substituted by one to three R.sub.6, wherein R.sub.6 is chosen from oxo, halogen, nitro, hydroxy, carboxy nitrile, amino, imino, guanidino, phenyl or C.sub.1-4 alkyl optionally substituted by one or more halogen atoms; R.sub.7 is hydrogen or C.sub.1-6 branched or unbranched alkyl optionally partially or fully halogenated; m is 0, 1, 2 or 3 and W is O or S or the pharmaceutically acceptable salts, acids, esters or isomers thereof.

2. The compound according to claim 1 wherein: R.sub.3 is ##STR83## R.sub.7 is hydrogen; E is --NH--; and W is O.

3. The compound according to claim 2 wherein: Ar is: naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indanyl, indenyl or indolyl each being optionally substituted by one or more R.sub.4 or R.sub.5 groups; X is: phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperidinyl, piperazinyl, pyridazinyl or pyrazinyl; each being optionally independently substituted with one to three C.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, nitrile, amino, mono- or di-(C.sub.1-3 alkyl)amino, mono- or di-(C.sub.1-3 alkylamino)carbonyl, NH.sub.2 C(O), C.sub.1-6 alkyl-S(O).sub.m or halogen; and Z is optionally substituted with one to three nitrile, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, amino, mono- or di-(C.sub.1-3 alkyl)amino, CONH.sub.2 or OH; or Z is optionally substituted by phenyl morpholinyl each in turn is optionally substituted by halogen, C.sub.1-3 alkyl or C.sub.1-3 alkoxy.

4. The compound according to claim 3 wherein: G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl, pyrazinyl, benzothiophenyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzooxazolyl, indanyl, indolyl, indolinyl, indolonyl or indolinonyl, wherein G is substituted by one R.sub.3 and further substituted by one or more R.sub.1 or R.sub.2 ; Ar is naphthyl; X is phenyl, imidazolyl, pyridinyl, pyrimidinyl, piperidinyl, piperazinyl, pyridazinyl or pyrazinyl each being optionally independently substituted with one to three C.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, nitrile, amino, mono- or di-(C.sub.1-3 alkyl)amino, mono- or di-(C.sub.1-3 alkylamino)carbonyl, NH.sub.2 C(O), C.sub.1-6 alkyl-S(O).sub.m or halogen; Y is: a bond or a C.sub.1-4 saturated carbon chain wherein one or more of the C atoms is optionally replaced by O, N or S and wherein Y is optionally independently substituted with nitrile or oxo; Z is optionally substituted with one to two C.sub.1-2 alkyl or C.sub.1-2 alkoxy; each R.sub.1 is independently: C.sub.1-5 alkyl branched or unbranched optionally partially or fully halogenated, wherein one or more C atoms are optionally independently replaced by O, N or S(O).sub.m, and wherein said C.sub.1-5 alkyl is optionally substituted with oxo, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl or bicyclohexanyl, each being optionally partially or fully halogenated and optionally substituted with one to three C.sub.1-3 alkyl groups optionally partially or fully halogenated, nitrile, hydroxyC.sub.1-3 alkyl or phenyl; oxo; C.sub.2-4 alkynyl optionally partially or fully halogenated wherein one or more methylene groups are optionally replaced by O, and optionally independently substituted with one to two oxo groups, hydroxy, C.sub.1-4 alkyl optionally substituted by one or more halogen atoms, nitrile, or mono- or di(C.sub.1-3 alkyl)amino optionally substituted by one or more halogen atoms; and each R.sub.2 is independently: a C.sub.1-4 alkyl optionally partially or fully halogenated, C.sub.1-4 alkoxy optionally partially or fully halogenated, bromo, chloro, fluoro, methoxycarbonyl, methyl-S(O).sub.m, ethyl-S(O).sub.m each optionally partially or fully halogenated or phenyl-S(O).sub.m.

5. The compound according to claim 4 wherein: G is: phenyl, pyridinyl, pyridonyl, 2-naphthyl, quinolinyl, isoquinolinyl, dihydrobenzofuranyl, indanyl, 5-indolyl, indolinyl, indolonyl, or indolinonyl, wherein G is substituted by one R.sub.3 and further substituted by one or more R.sub.1 or R.sub.2 ; Ar is 1-naphthyl; X is: phenyl, imidazolyl, pyridinyl, pyrimidinyl, piperidinyl, piperazinyl, pyridazinyl or pyrazinyl and wherein X is attached to the 4-position of Ar; Y is: a bond or --CH.sub.2 --, --CH.sub.2 CH.sub.2 --, O--CH.sub.2 CH.sub.2 --, --C(O)--, --O--, --S--, --NH--CH.sub.2 CH.sub.2 --, --N(CH.sub.3)--, CH.sub.2 (CN)CH.sub.2 --NH--CH.sub.2 or --NH--; Z is: morpholinyl; R.sub.1 is: C.sub.1-5 alkyl optionally partially or fully halogenated wherein one or more C atoms are optionally independently replaced by O or N, and wherein said C.sub.1-5 alkyl is optionally substituted with oxo; cyclopropyl, cyclopentanyl, cyclohexanyl and bicyclopentanyl optionally substituted with one to three methyl groups optionally partially or fully halogenated, nitrile, hydroxymethyl or phenyl; R.sub.2 is: C.sub.1-4 alkoxy optionally partially or fully halogenated, bromo, chloro, fluoro, nitrile, nitro, amino; and R.sub.a and R.sub.b are each independently hydrogen, C.sub.1-5 alkyl, phenylC.sub.0-5 alkyl optionally substituted on the phenyl by C.sub.1-6 alkyl, halogen, hydroxy, carboxy, oxo, amino, imino, nitro or nitrile; or R.sub.a and R.sub.b together with the nitrogen atom to which they are attached form a morpholinyl, piperidinyl, piperazinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl and isothiazolyl, each optionally substituted by one to two R.sub.6.

6. The compound according to claim 5, wherein: G is: phenyl or pyridinyl wherein G is substituted by one R.sub.3 and further substituted by one or more R.sub.1 or R.sub.2 ; X is: phenyl, imidazolyl, pyridinyl, pyrimidinyl or pyrazinyl; Y is: a bond, --OCH.sub.2 CH.sub.2 --, --CH.sub.2 CH.sub.2 --, --O--, CH.sub.2 (CN)CH.sub.2 --NH--CH.sub.2, --CH.sub.2 --, --NH--CH.sub.2 CH.sub.2 -- or --NH--; Z is: morpholin-4yl; R.sub.1 is: tert-butyl, sec-butyl, phenyl, or cyclohexanyl; R.sub.a and R.sub.b are each independently hydrogen, a C.sub.1-4 alkyl, phenyl, benzyl wherein the phenyl or phenyl portion of the benzyl are optionally substituted by methyl, halogen, hydroxy, carboxy, amino; or R.sub.a and R.sub.b together with the nitrogen atom to which they are attached form a morpholinyl, piperidinyl, piperazinyl or pyrrolidinyl, each optionally substituted by one to two R.sub.6 ; and R.sub.6 is C.sub.1-4 alkyl, halogen, nitro, nitrile, hydroxy, carboxy or oxo.

7. The compound according to claim 6 wherein G is phenyl substituted by R.sub.3 and one to two R.sub.1 or R.sub.2 ; X is phenyl or pyridin-3yl; R.sub.a and R.sub.b are each independently hydrogen, a C.sub.1-3 alkyl, phenyl or benzyl; or R.sub.a and R.sub.b together with the nitrogen atom to which they are attached form a morpholinyl, piperidinyl, piperazinyl or pyrrolidinyl, each optionally substituted by one to two R.sub.6 ; and R.sub.6 is C.sub.1-3 alkyl or halogen; Y is: a bond, --OCH.sub.2 CH.sub.2 --, --CH.sub.2 CH.sub.2 --, --O--, --CH.sub.2 --, --NH--CH.sub.2 CH.sub.2 -- or --NH--.

8. The compound according to claim 7 wherein: the attachment of X to Ar and Y is at the following X positions: 3-,6-pyridinyl or 1-,4-phenyl, respectively; Y is --CH.sub.2 -- and R.sub.6 is methyl or ethyl.

9. The compound according to claim 1 wherein: R.sub.3 is: ##STR84## E is --NH-- and W is O.

10. The compound according to claim 9 wherein: Ar is: naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indanyl, indenyl or indolyl each being optionally substituted by one or more R.sub.4 or R.sub.5 groups; X is: phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperidinyl, piperazinyl, pyridazinyl or pyrazinyl; each being optionally independently substituted with one to three C.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, nitrile, amino, mono- or di-(C.sub.1-3 alkyl)amino, mono- or di-(C.sub.1-3 alkylamino)carbonyl, NH.sub.2 C(O), C.sub.1-6 alkyl-S(O).sub.m or halogen; Z is: morpholinyl optionally substituted with one to three nitrile, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, amino, mono- or di-(C.sub.1-3 alkyl)amino, CONH.sub.2 or OH; or Z is optionally substituted by phenyl, heterocycle or heteroaryl as hereinabove described in this paragraph each in turn is optionally substituted by halogen, C.sub.1-3 alkyl or C.sub.1-3 alkoxy; and R.sub.a is a C.sub.1-10 saturated or unsaturated branched or unbranched carbon chain, wherein one of the C atoms is optionally replaced by O or N and optionally substituted by oxo; or R.sub.a is C.sub.3-7 cycloalkylC.sub.0-6 alkyl, phenylC.sub.0-6 alkyl, heterocycleC.sub.0-6 alkyl or heteroarylC.sub.0-6 alkyl wherein the C.sub.0-6 alkyl portion is optionally substituted by oxo and wherein the heterocycle or heteroaryl moiety is chosen from morpholinyl, pyridinyl, piperidinyl, piperazinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxazoyl, [1,3,4]oxadiazol, triazolyl, tetrazolyl, isoxazolyl and isothiazolyl, each C.sub.3-7 cycloalkyl, phenyl, heterocycle or heteroaryl is optionally substituted by C.sub.1-6 alkyl, halogen, hydroxy, carboxy, oxo, amino, nitro or nitrile.

11. The compound according to claim 10 wherein: G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl, pyrazinyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzothiophenyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzooxazolyl, indanyl, indolyl, indolinyl, indolonyl or indolinonyl, wherein G is substituted by one R.sub.3 and further substituted by one or more R.sub.1 or R.sub.2 ; Ar is naphthyl; X is phenyl, imidazolyl, pyridinyl, pyrimidinyl, piperidinyl, piperazinyl, pyridazinyl or pyrazinyl each being optionally independently substituted with one to three C.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, nitrile, amino, mono- or di-(C.sub.1-3 alkyl)amino, mono- or di-(C.sub.1-3 alkylamino)carbonyl, NH.sub.2 C(O), C.sub.1-6 alkyl-S(O).sub.m or halogen; Y is: a bond or a C.sub.1-4 saturated carbon chain wherein one or more of the C atoms is optionally replaced by O, N or S and wherein Y is optionally independently substituted with nitrile or oxo; Z is: morpholinyl optionally substituted with one to two C.sub.1-2 alkyl or C.sub.1-2 alkoxy; each R.sub.1 is independently: C.sub.1-5 alkyl branched or unbranched optionally partially or fully halogenated, wherein one or more C atoms are optionally independently replaced by O, N or S(O).sub.m, and wherein said C.sub.1-5 alkyl is optionally substituted with oxo, dioxolanyl, pyrrolidinyl, furyl or phenyl each optionally substituted with one to three halogen, C.sub.1-3 alkyl which is optionally partially or fully halogenated, hydroxy, nitrile and C.sub.1-3 alkoxy which is optionally partially or fully halogenated; cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl or bicyclohexanyl, each being optionally partially or fully halogenated and optionally substituted with one to three C.sub.1-3 alkyl groups optionally partially or fully halogenated, nitrile, hydroxyC.sub.1-3 alkyl or phenyl; oxo; C.sub.2-4 alkynyl optionally partially or fully halogenated wherein one or more methylene groups are optionally replaced by O, and optionally independently substituted with one to two oxo groups, hydroxy, pyrroldinyl, pyrrolyl, tetrahydropyranyl, C.sub.1-4 alkyl optionally substituted by one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono- or di(C.sub.1-3 alkyl)amino optionally substituted by one or more halogen atoms; and each R.sub.2 is independently: a C.sub.1-4 alkyl optionally partially or fully halogenated, C.sub.1-4 alkoxy optionally partially or fully halogenated, bromo, chloro, fluoro, methoxycarbonyl, methyl-S(O).sub.m, ethyl-S(O).sub.m each optionally partially or fully halogenated or phenyl-S(O).sub.m ; or R.sub.2 is mono- or di-C.sub.1-3 acylamino, amino-S(O).sub.m or S(O).sub.m amino wherein the N atom is mono- or di-substituted by C.sub.1-3 alkyl or phenyl, nitrile, nitro or amino.

12. The compound according to claim 11 wherein: G is: phenyl, pyridinyl, pyridonyl, 2-naphthyl, quinolinyl, isoquinolinyl, dihydrobenzofuranyl, indanyl, 5-indolyl, indolinyl, indolonyl, or indolinonyl, wherein G is substituted by one R.sub.3 and further substituted by one or more R.sub.1 or R.sub.2 ; Ar is 1-naphthyl; X is: phenyl, imidazolyl, pyridinyl, pyrimidinyl, piperidinyl, piperazinyl, pyridazinyl or pyrazinyl and wherein X is attached to the 4-position of Ar; Y is: a bond or --CH.sub.2 --, --CH.sub.2 CH.sub.2 --, O--CH.sub.2 CH.sub.2 --, >C(O), --O--, --S--, --NH--CH.sub.2 CH.sub.2 --, --N(CH.sub.3)--, CH.sub.2 (CN)CH.sub.2 --NH--CH.sub.2 or --NH--; Z is: morpholinyl optionally substituted by C.sub.1-2 alkyl or C.sub.1-2 alkoxy; R.sub.1 is: C.sub.1-5 alkyl optionally partially or fully halogenated wherein one or more C atoms are optionally independently replaced by O or N, and wherein said C.sub.1-5 alkyl is optionally substituted with oxo, dioxolanyl, pyrrolidinyl, furyl or phenyl optionally substituted by C.sub.1-3 alkoxy; cyclopropyl, cyclopentanyl, cyclohexanyl and bicyclopentanyl optionally substituted with one to three methyl groups optionally partially or fully halogenated, nitrile, hydroxymethyl or phenyl; or 2-tetrahydrofuranyl substituted by methyl; propynyl substituted hydroxy or tetrahydropyran-2-yloxy; R.sub.2 is: is C.sub.1-4 alkoxy optionally partially or fully halogenated, mono- or di-C.sub.1-3 acylamino, amino-S(O).sub.m or S(O).sub.m amino wherein the N atom is mono- or di-substituted by C.sub.1-3 alkyl or phenyl, bromo, chloro, fluoro, nitrile, nitro, amino, methylsulfonyl optionally partially or fully halogenated or phenylsulfonyl; and R.sub.a is C.sub.1-4 alkyl optionally substituted by C.sub.1-3 alkoxy, mono- or di-C.sub.1-3 alkylamino, mono- or di-C.sub.1-3 alkylaminocarbonyl; or R.sub.a is heterocycleC.sub.0-3 alkyl wherein the heterocycle is chosen from morpholinyl, tetrahydrofuranyl, pyrrolidinyl, 2,5-dioxo-pyrrolidinyl, piperidinyl, 2-oxo-piperidinyl and 3-oxo-morpholinyl, heteroarylC.sub.0-3 alkyl wherein the C.sub.0-3 alkyl portion is optionally substituted by oxo and the heteroaryl is chosen from pyridinyl, imidazolyl, pyrazolyl, thiazolyl and oxazolyl or R.sub.a is C.sub.3-6 cycloalkylC.sub.0-3 alkyl.

13. The compound according to claim 12 wherein: G is: phenyl or pyridinyl, wherein G is substituted by one R.sub.3 and further substituted by one or more R.sub.1 or R.sub.2 ; X is: phenyl, imidazolyl, pyridinyl, pyrimidinyl or pyrazinyl; Y is: a bond, --OCH.sub.2 CH.sub.2 --, --CH.sub.2 CH.sub.2 --, --O--, CH.sub.2 (CN)CH.sub.2 --NH--CH.sub.2, --CH.sub.2 --, >C(O), --NH--CH.sub.2 CH.sub.2 -- or --NH--; Z is: morpholinyl, optionally substituted by C.sub.1-2 alkyl or C.sub.1-2 alkoxy; R.sub.1 is: tert-butyl, sec-butyl, tert-amyl, phenyl, tetrahydropyran-2-yloxypropynyl, hydroxypropynyl, trihalomethyl, 2,2-diethylpropionyl or cyclohexanyl; R.sub.2 is: C.sub.1-4 alkoxy optionally partially or fully halogenated, chloro, nitro, amino, nitrile, methylsulfonylamino, diacetylamino, phenylsulfonylamino, N,N -di(methylsulfonyl)amino, methylsulfonyl or trihalomethylsulfonyl; and R.sub.a is C.sub.1-4 alkyl optionally substituted by C.sub.1-3 alkoxy, mono- or di-C.sub.1-3 alkylamino, mono- or di-C.sub.1-3 alkylaminocarbonyl; or R.sub.a is heterocycleC0-2 alkyl wherein the heterocycle is chosen from morpholinyl, tetrahydrofuranyl, pyrrolidinyl, 2,5-dioxo-pyrrolidinyl, piperidinyl, 2-oxo-piperidinyl and 3-oxo-morpholinyl, heteroarylC0-2 alkyl wherein the heteroaryl is chosen from piperidinyl and oxazolyl or R.sub.a is C.sub.3-6 cycloalkyl C.sub.0-2 alkyl.

14. The compound according to claim 13 wherein: G is phenyl substituted by R.sub.3 and one to two R.sub.1 or R.sub.2 ; X is phenyl, pyridinyl, pyrimidinyl or pyrazinyl; R.sub.a is C.sub.1-4 alkyl optionally substituted by C.sub.1-3 alkoxy, mono- or di-C.sub.1-3 alkylamino, mono- or di-C.sub.1-3 alkylaminocarbonyl; or R.sub.a is heterocycleC.sub.0-2 alkyl wherein the heterocycle is chosen from morpholin-4-yl, tetrahydrofuran-2-yl, pyrrolidin-1 or 2-yl, 2,5-dioxo-pyrrolidin-1-yl, piperidin-2-yl, 2-oxo-piperidin-3-yl and 3-oxo-morpholin-4-yl, heteroarylC.sub.0-2 alkyl wherein the heteroaryl is chosen from piperidin-3 or 4-yl and oxazol-5-yl or R.sub.a is cyclopropylmethyl; Y is: --O--, --CH.sub.2 -- or >C(O); and Z is morpholin-4-yl optionally substituted by C.sub.1-2 alkyl.

15. The compound according to claim 14 wherein: the attachment of X to Ar and Y is at the following X positions: 3,6 pyridinyl, 1,4 phenyl, 2,5 pyrimidinyl and 2,5 pyrazinyl, respectively; Y is --CH.sub.2 -- or >C(O).

16. A compound wherein the compound is N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-nap hthalen-1-yl]-ureido}-phenyl)-2-morpholin-4-yl-2-oxo-acetamide or the pharmaceutically acceptable salts, acids, esters or isomers thereof.

17. A compound chosen from N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-nap hthalen-1-yl]-ureido}-phenyl)-N',N'-diethyl-oxalamide; N-(5-tert-Butyl-2-methoxy-3-{3-[4-(4-morpholin-4-ylmethyl-phenyl)-naphthale n-1-yl]-ureido}-phenyl)-N'-methyl-oxalamide; N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-nap hthalen-1-yl]-ureido}-phenyl)-N'-ethyl-oxalamide; N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-nap hthalen-1-yl]-ureido}-phenyl)-N',N'-dimethyl-oxalamide; N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-nap hthalen-1-yl]-ureido}-phenyl)-2-oxo-2-pyrrolidin-1-yl-acetamide; N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-nap hthalen-1-yl]-ureido}-phenyl)-2-oxo-2-piperidin-1-yl-acetamide; N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-nap hthalen-1-yl]-ureido}-phenyl)-2-oxo-2-piperazin-1-yl-acetamide and N-(5-tert-Butyl-2-methoxy-3-{3-[4-(4-morpholin-4-ylmethyl-phenyl)-naphthale n-1-yl]-ureido}-phenyl)-2-oxo-2-piperazin-1-yl-acetamide or the pharmaceutically acceptable salts, acids, esters or isomers thereof.

18. A compound chosen from (5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-napht halen-1yl]-ureido}-phenyl)-carbamic acid methyl ester; (5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-napht halen-1yl]-ureido}-phenyl)-carbamic acid isopropyl ester; (5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-napht halen-1yl]-ureido}-phenyl)-carbamic acid 2-methoxy-ethyl ester; (5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-napht halen-1yl]-ureido}-phenyl)-carbamic acid ethyl ester and (5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-napht halen-1-yl]-ureido}-phenyl)-carbamic acid 2-morpholin-4-yl-ethyl ester or the pharmaceutically acceptable salts, acids, esters or isomers thereof.

19. A compound chosen from (5-tert-Butyl-2-methoxy-3-{3-[4-(2-morpholin-4-ylmethyl-pyrimidin-5-yl)-nap hthalen-1-yl]-ureido}-phenyl)-carbamic acid cyclopropylmethyl ester; (5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-napht halen-1yl]-ureido}-phenyl)-carbamic acid tert-butyl ester; (5-tert-Butyl-2-methoxy-3-{3-[4-(2-morpholin-4-ylmethyl-pyrimidin-5-yl)-nap hthalen-1-yl]-ureido}-phenyl)-carbamic acid tetrahydro-furan-2-ylmethyl ester; (5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-napht halen-1yl]-ureido}-phenyl)-carbamic acid tetrahydro-furan-2-ylmethyl ester; (5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-napht halen-1yl]-ureido}-phenyl)-carbamic acid 1-methyl-pyrrolidin-2-ylmethyl ester; (5-tert-Butyl-2-methoxy-3-{3-[4-(4-morpholin-4-ylmethyl-phenyl)-naphthalen- 1-yl]-ureido}-phenyl)-carbamic acid 1-methyl-pyrrolidin-2-ylmethyl ester; (5-tert-Butyl-2-methoxy-3-{3-[4-(4-morpholin-4-ylmethyl-phenyl)-naphthalen- 1-yl]-ureido}-phenyl)-carbamic acid 2-pyrrolidin-1-yl-ethyl ester; (5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-napht halen-1-yl]-ureido}-phenyl)-carbamic acid 2-dimethylamino-ethyl ester; (5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-napht halen-1-yl]-ureido}-phenyl)-carbamic acid 2-(2,5-dioxo-pyrrolidin-1-yl)-ethyl ester; [5-tert-Butyl-2-methoxy-3-(3-{4-[2-(morpholine-4-carbonyl)-pyrimidin-5-yl]- naphthalen-1-yl}-ureido)-phenyl]-carbamic acid 2-dimethylamino-propyl ester; [5-tert-Butyl-2-methoxy-3-(3-{4-[5-(morpholine-4-carbonyl)-pyrazin-2-yl]-na phthalen-1-yl}-ureido)-phenyl]-carbamic acid 2-dimethylamino-propyl ester; (5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-napht halen-1-yl]-ureido}-phenyl)-carbamic acid 2-dimethylamino-2-methyl-propyl ester; [5-tert-Butyl-2-methoxy-3-(3-{4-[6-(morpholine-4-carbonyl)-pyridin-3-yl]-na phthalen-1-yl}-ureido)-phenyl]-carbamic acid 1-methyl-piperidin-2-ylmethyl ester; [5-tert-Butyl-2-methoxy-3-(3-{4-[6-(morpholine-4-carbonyl)-pyridin-3-yl]-na phthalen-1-yl }-ureido)-phenyl]-carbamic acid dimethylcarbamoylmethyl ester; (5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-napht halen-1-yl]-ureido}-phenyl)-carbamic acid methylcarbamoylmethyl ester; (5-tert-Butyl-2-methoxy-3-{3-[4-(2-morpholin-4-ylmethyl-pyrimidin-5-yl)-nap hthalen-1-yl]-ureido}-phenyl)-carbamic acid methylcarbamoylmethyl ester; [5-tert-Butyl-2-methoxy-3-(3-{4-[2-(morpholine-4-carbonyl)-pyrimidin-5-yl]- naphthalen-1-yl}-ureido)-phenyl]-carbamic acid carbamoylmethyl ester; (5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-napht halen-1-yl]-ureido}-phenyl)-carbamic acid carbamoylmethyl ester; (5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-napht halen-1-yl]-ureido}-phenyl)-carbamic acid 2-oxo-2-pyrrolidin-1-yl-ethyl ester; (5-tert-Butyl-2-methoxy-3-{3-[4-(5-morpholin-4-ylmethyl-pyrazin-2-yl)-napht halen-1-yl]-ureido}-phenyl)-carbamic acid 2-oxo-piperidin-3-yl ester; (5-tert-Butyl-2-methoxy-3-{3-[4-(5-morpholin-4-ylmethyl-pyrazin-2-yl)-napht halen-1-yl]-ureido}-phenyl)-carbamic acid pyridin-3-ylmethyl ester; [5-tert-Butyl-2-methoxy-3-(3-{4-[5-(morpholine-4-carbonyl)-pyrazin-2-yl]-na phthalen-1-yl}-ureido)-phenyl]-carbamic acid oxazol-5-ylmethyl ester; (5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-napht halen-1-yl]-ureido}-phenyl)-carbamic acid oxazol-5-ylmethyl ester; (5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-napht halen-1-yl]-ureido}-phenyl)-carbamic acid pyridin-4-ylmethyl ester; (5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-napht halen-1-yl]-ureido}-phenyl)-carbamic acid 2-(3-oxo-morpholin-4-yl)-ethyl ester; and or the pharmaceutically acceptable derivatives thereof.

20. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to claim 1.

21. A method of treating a disease or condition selected from rheumatoid arthritis, inflammatory bowel disease, osteoarthritis, Crohn's disease, ulcerative colitis, Guillain-Barre syndrome, psoriasis, graft versus host disease, systemic lupus erythematosus, percutaneous transluminal coronary angioplasty, toxic shock syndrome, acute and chronic pain, contact dermatitis, atherosclerosis, traumatic arthritis, glomerulonephritis, reperfusion injury, bone resorption disease, chronic obstructive pulmonary disease, asthma, myocardial infarction, thermal injury, adult respiratory distress syndrome (ARDS), multiple organ injury secondary to trauma, dermatoses with acute inflammatory components, acute purulent meningitis, necrotizing entrerocolitis, syndromes associated with hermodialysis, leukopherisis and granulocyte transfusion comprising administering to a patient a threapeutically effective amount of a compound according to a claim 1.

22. The method according to claim 21 wherein the disease is selected from rheumatoid arthritis, osteoarthritis, Crohn's disease, psoriasis, ulcerative colitis, osteoporosis and chronic obstructive pulmonary disease.

23. The method according to claim 22 wherein the disease is selected from rheumatoid arthritis, Crohn's disease, psoriasis and chronic obstructive pulmonary disease.

24. A method of making a compound of the formula(I) according to claim 1, comprising: a) reacting an arylamine with 2,2,2-trichloroethylchloroformate in a suitable halogenated solvent with a suitable base at 0-85.degree. C. for about 2-24 hours: ##STR85## b) isolating and subsequently reacting the product of step a) with an arylamine shown below in a non-protic anhydrous solvent at 0-110.degree. C. for about 2-24 hours, to produce a compound of the formula (I): ##STR86## wherein E is N--H, W is O and G, Ar, X, Y and Z are as defined in claim 1.

Description

TECHNICAL FIELD OF THE INVENTION

This invention relates to novel compounds which inhibit production of cytokines involved in inflammatory processes and are thus useful for treating diseases and pathological conditions involving inflammation such as chronic inflammatory disease. This invention also relates to processes for preparing these compounds and to pharmaceutical compositions comprising these compounds.

BACKGROUND OF THE INVENTION

Tumor necrosis factor (TNF) and interleukin-1 (IL-1) are important biological entities collectively referred to as proinflammatory cytokines. These, along with several other related molecules, mediate the inflammatory response associated with the immunological recognition of infectious agents. The inflammatory response plays an important role in limiting and controlling pathogenic infections.

Elevated levels of proinflammatory cytokines are also associated with a number of diseases of autoimmunity such as toxic shock syndrome, rheumatoid arthritis, osteoarthritis, diabetes and inflammatory bowel disease (Dinarello, C. A., et al., 1984, Rev. Infect. Disease 6:51). In these diseases, chronic elevation of inflammation exacerbates or causes much of the pathophysiology observed. For example, rheumatoid synovial tissue becomes invaded with inflammatory cells that result in destruction to cartilage and bone (Koch, A. E., et al., 1995, J. Invest. Med. 43: 28-38). Studies suggest that inflammatory changes mediated by cytokines may be involved in the pathogenesis of restenosis after percutaneous transluminal coronary angioplasty (PTCA) (Tashiro, H., et al., 2001 Mar, Coron Artery Dis 12(2):107-13). An important and accepted therapeutic approach for potential drug intervention in these diseases is the reduction of proinflammatory cytokines such as TNF (also referred to in its secreted cell-free form as TNF.alpha.) and IL-1.beta.. A number of anti-cytokine therapies are currently in clinical trials. Efficacy has been demonstrated with a monoclonal antibody directed against TNF.alpha. in a number of autoimmune diseases (Heath, P., "CDP571: An Engineered Human IgG4 Anti-TNF.alpha. Antibody" IBC Meeting on Cytokine Antagonists, Philadelphia, Pa., Apr. 24-5, 1997). These include the treatment of rheumatoid arthritis, Crohn's disease and ulcerative colitis (Rankin, E. C. C., et al., 1997, British J. Rheum. 35: 334-342 and Stack, W. A., et al., 1997, Lancet 349: 521-524). The monoclonal antibody is thought to function by binding to both soluble TNF.alpha. and to membrane bound TNF.

A soluble TNF.alpha. receptor has been engineered that interacts with TNF.alpha.. The approach is similar to that described above for the monoclonal antibodies directed against TNF.alpha.; both agents bind to soluble TNF.alpha., thus reducing its concentration. One version of this construct, called Enbrel (Immunex, Seattle, Wash.) recently demonstrated efficacy in a Phase III clinical trial for the treatment of rheumatoid arthritis (Brower et al., 1997, Nature Biotechnology 15: 1240). Another version of the TNF.alpha. receptor, Ro 45-2081 (Hoffman-LaRoche Inc., Nutley, N.J.) has demonstrated efficacy in various animal models of allergic lung inflammation and acute lung injury. Ro 45-2081 is a recombinant chimeric molecule constructed from the soluble 55 kDa human TNF receptor fused to the hinge region of the heavy chain IgG1 gene and expressed in eukaryotic cells (Renzetti, et al., 1997, Inflamm. Res. 46: S143).

IL-1 has been implicated as an immunological effector molecule in a large number of disease processes. IL-1 receptor antagonist (IL-1ra) had been examined in human clinical trials. Efficacy has been demonstrated for the treatment of rheumatoid arthritis (Antril, Amgen). In a phase III human clinical trial IL-1ra reduced the mortality rate in patients with septic shock syndrome (Dinarello, 1995, Nutrution 11, 492). Osteoarthritis is a slow progressive disease characterized by destruction of the articular cartilage. IL-1 is detected in synovial fluid and in the cartilage matrix of osteoarthritic joints.

Antagonists of IL-1 have been shown to diminish the degradation of cartilage matrix components in a variety of experimental models of arthritis (Chevalier, 1997, Biomed Pharmacother. 51, 58). Nitric oxide (NO) is a mediator of cardiovascular homeostasis, neurotransmission and immune function; recently it has been shown to have important effects in the modulation of bone remodeling. Cytokines such as IL-1 and TNF are potent stimulators of NO production. NO is an important regulatory molecule in bone with effects on cells of the osteoblast and osteoclast lineage (Evans, et al., 1996, J Bone Miner Res. 11, 300). The promotion of beta-cell destruction leading to insulin dependent diabetes mellitus shows dependence on IL-1. Some of this damage may be mediated through other effectors such as prostaglandins and thromboxanes. IL-1 can effect this process by controlling the level of both cyclooxygenase II and inducible nitric oxide synthetase expression (McDaniel et al., 1996, Proc Soc Exp Biol Med. 211, 24).

Inhibitors of cytokine production are expected to block inducible cyclooxygenase (COX-2) expression. COX-2 expression has been shown to be increased by cytokines and it is believed to be the isoform of cyclooxygenase responsible for inflammation (M. K. O'Banion et al., Proc. Natl. Acad. Sci. U.S.A, 1992, 89, 4888.) Accordingly, inhibitors of cytokines such as IL-1 would be expected to exhibit efficacy against those disorders currently treated with COX inhibitors such as the familiar NSAIDs. These disorders include acute and chronic pain as well as symptoms of inflammation and cardiovascular disease.

Elevation of several cytokines have been demonstrated during active inflammatory bowel disease (IBD). A mucosal imbalance of intestinal IL-1 and IL-1ra is present in patients with IBD. Insufficient production of endogenous IL-1ra may contribute to the pathogenesis of IBD (Cominelli, et al, 1996, Aliment Pharmacol Ther. 10, 49). Alzheimer disease is characterized by the presence of beta-amyloid protein deposits, neurofibrillary tangles and cholinergic dysfunction throughout the hippocampal region. The structural and metabolic damage found in Alzheimer disease is possibly due to a sustained elevation of IL-I (Holden, et al., 1995, Med Hypotheses, 45, 559). A role for IL-1 in the pathogenesis of human immunodeficiency virus (HIV) has been identified.

IL-1ra showed a clear relationship to acute inflammatory events as well as to the different disease stages in the pathophysiology of HIV infection (Kreuzer, et al., 1997, Clin Exp Immunol. 109, 54). IL-1 and TNF are both involved in periodontal disease. The destructive process associated with periodontal disease may be due to a disregulation of both IL-1 and TNF (Howells, 1995, Oral Dis. 1, 266).

Proinflammatory cytokines such as TNF.alpha. and IL-1.beta. are also important mediators of septic shock and associated cardiopulmonary dysfunction, acute respiratory distress syndrome (ARDS) and multiple organ failure. In a study of patients presenting at a hospital with sepsis, a correlation was found between TNF.alpha. and IL-6 levels and septic complications (Terregino et al., 2000, Ann. Emerg. Med., 35, 26). TNF.alpha. has also been implicated in cachexia and muscle degradation, associated with HIV infection (Lahdiverta et al., 1988, Amer. J. Med., 85, 289). Obesity is associated with an increase incidence of infection, diabetes and cardiovascular disease. Abnormalities in TNF.alpha. expression have been noted for each of the above conditions (Loffreda, et al., 1998, FASEB J. 12, 57). It has been proposed that elevated levels of TNF.alpha. are involved in other eating related disorders such as anorexia and bulimia nervosa. Pathophysiological parallels are drawn between anorexia nervosa and cancer cachexia (Holden, et al., 1996, Med Hypotheses 47, 423). An inhibitor of TNF.alpha. production, HU-211, was shown to improve the outcome of closed brain injury in an experimental model (Shohami, et al., 1997, J Neuroimmunol. 72, 169). Atherosclerosis is known to have an inflammatory component and cytokines such as IL-1 and TNF have been suggested to promote the disease. In an animal model an IL-1 receptor antagonist was shown to inhibit fatty streak formation (Elhage et al., 1998, Circulation, 97, 242).

TNF.alpha. levels are elevated in airways of patients with chronic obstructive pulmonary disease and it may contribute to the pathogenesis of this disease (M. A. Higham et al., 2000, Eur. Respiratory J., 15, 281). Circulating TNF.alpha. may also contribute to weight loss associated with this disease (N. Takabatake et al., 2000, Amer. J Resp. & Crit. Care Med.,161 (4 Pt 1), 1179). Elevated TNF.alpha. levels have also been found to be associated with congestive heart failure and the level has been correlated with severity of the disease (A. M. Feldman et al., 2000, J. Amer. College of Cardiology, 35, 537). In addition, TNF.alpha. has been implicated in reperfusion injury in lung (Bodjesson et al., 2000, Amer. J. Physiol., 278, L3-12), kidney (Lemay et al., 2000, Transplantation, 69, 959), and the nervous system (Mitsui et al., 1999, Brain Res., 844, 192).

TNF.alpha. is also a potent osteoclastogenic agent and is involved in bone resorption and diseases involving bone resorption (Abu-Amer et al., 2000, J. Biol. Chem., 275, 27307). It has also been found highly expressed in chondrocytes of patients with traumatic arthritis (Melchiorri et al., 2000, Arthritis and Rheumatism, 41, 2165). TNF.alpha. has also been shown to play a key role in the development of glomerulonephritis (Le Hir et al., 1998, Laboratory Investigation, 78, 1625).

The abnormal expression of inducible nitric oxide synthetase (iNOS) has been associated with hypertension in the spontaneously hypertensive rat (Chou et al., 1998, Hypertension, 31, 643). IL-1 has a role in the expression of iNOS and therefore may also have a role in the pathogenesis of hypertension (Singh et al., 1996, Amer. J. Hypertension, 9, 867).

IL-1 has also been shown to induce uveitis in rats which could be inhibited with IL-1 blockers. (Xuan et al., 1998, J. Ocular Pharmacol. and Ther., 14, 31). Cytokines including IL-1, TNF and GM-CSF have been shown to stimulate proliferation of acute myelogenous leukemia blasts (Bruserud, 1996, Leukemia Res. 20, 65). IL-1 was shown to be essential for the development of both irritant and allergic contact dermatitis. Epicutaneous sensitization can be prevented by the administration of an anti-IL-1 monoclonal antibody before epicutaneous application of an allergen (Muller, et al., 1996, Am J Contact Dermat. 7, 177). Data obtained from IL-1 knock out mice indicates the critical involvement in fever for this cytokine (Kluger et al., 1998, Clin Exp Pharmacol Physiol. 25, 141). A variety of cytokines including TNF, IL-1, IL-6 and IL-8 initiate the acute-phase reaction which is stereotyped in fever, malaise, myalgia, headaches, cellular hypermetabolism and multiple endocrine and enzyme responses (Beisel, 1995, Am J Clin Nutr. 62, 813). The production of these inflammatory cytokines rapidly follows trauma or pathogenic organism invasion.

Other proinflammatory cytokines have been correlated with a variety of disease states. IL-8 correlates with influx of neutrophils into sites of inflammation or injury. Blocking antibodies against IL-8 have demonstrated a role for IL-8 in the neutrophil associated tissue injury in acute inflammation (Harada et al, 1996, Molecular Medicine Today 2, 482). Therefore, an inhibitor of IL-8 production may be useful in the treatment of diseases mediated predominantly by neutrophils such as stroke and myocardial infarction, alone or following thrombolytic therapy, thermal injury, adult respiratory distress syndrome (ARDS), multiple organ injury secondary to trauma, acute glomerulonephritis, dermatoses with acute inflammatory components, acute purulent meningitis or other central nervous system disorders, hemodialysis, leukopherisis, granulocyte transfusion associated syndromes, and necrotizing enterocolitis. Rhinovirus triggers the production of various proinflammatory cytokines, predominantly IL-8, which results in symptomatic illnesses such as acute rhinitis (Winther et al., 1998, Am J Rhinol. 12, 17).

Other diseases that are effected by IL-8 include myocardial ischemia and reperfusion, inflammatory bowel disease and many others.

The proinflammatory cytokine IL-6 has been implicated with the acute phase response. IL-6 is a growth factor in a number in oncological diseases including multiple myeloma and related plasma cell dyscrasias (Treon, et al., 1998, Current Opinion in Hematology 5:42). It has also been shown to be an important mediator of inflammation within the central nervous system. Elevated levels of IL-6 are found in several neurological disorders including AIDS dementia complex, Alzheimer's disease, multiple sclerosis, systemic lupus erythematosus, CNS trauma and viral and bacterial meningitis (Gruol, et al., 1997, Molecular Neurobiology 15: 307). IL-6 also plays a significant role in osteoporosis. In murine models it has been shown to effect bone resorption and to induce osteoclast activity (Ershler et al., 1997, Development and Comparative Immunol. 21:487). Marked cytokine differences, such as IL-6 levels, exist in vivo between osteoclasts of normal bone and bone from patients with Paget's disease (Mills, et al., 1997, Calcif Tissue Int. 61, 16). A number of cytokines have been shown to be involved in cancer cachexia. The severity of key parameters of cachexia can be reduced by treatment with anti IL-6 antibodies or with IL-6 receptor antagonists (Strassmann, et al., 1995, Cytokins Mol Ther. 1, 107). Several infectious diseases, such as influenza, indicate IL-6 and IFN alpha as key factors in both symptom formation and in host defense (Hayden, et al., 1998, J Clin Invest. 101, 643). Overexpression of IL-6 has been implicated in the pathology of a number of diseases including multiple myeloma, rheumatoid arthritis, Castleman's disease, psoriasis and post-menopausal osteoporosis (Simpson, et al., 1997, Protein Sci. 6, 929). Compounds that interfered with the production of cytokines including IL-6, and TNF were effective in blocking a passive cutaneous anaphylaxis in mice (Scholz et al., 1998, J. Med. Chem., 41, 1050).

GM-CSF is another proinflammatory cytokine with relevance to a number of therapeutic diseases. It influences not only proliferation and differentiation of stem cells but also regulates several other cells involved in acute and chronic inflammation. Treatment with GM-CSF has been attempted in a number of disease states including bum-wound healing, skin-graft resolution as well as cytostatic and radiotherapy induced mucositis (Masucci, 1996, Medical Oncology 13: 149). GM-CSF also appears to play a role in the replication of human immunodeficiency virus (HIV) in cells of macrophage lineage with relevance to AIDS therapy (Crowe et al., 1997, Journal of Leukocyte Biology 62, 41). Bronchial asthma is characterised by an inflammatory process in lungs. Involved cytokines include GM-CSF amongst others (Lee, 1998, J R Coll Physicians Lond 32, 56).

Interferon .gamma. (IFN .gamma.) has been implicated in a number of diseases. It has been associated with increased collagen deposition that is a central histopathological feature of graft-versus-host disease (Parkman, 1998, Curr Opin Hematol. 5, 22). Following kidney transplantation, a patient was diagnosed with acute myelogenous leukemia. Retrospective analysis of peripheral blood cytokines revealed elevated levels of GM-CSF and IFN .gamma.. These elevated levels coincided with a rise in peripheral blood white cell count (Burke, et al., 1995, LeukLymphoma. 19, 173). The development of insulin-dependent diabetes (Type 1) can be correlated with the accumulation in pancreatic islet cells of T-cells producing IFN .gamma. (Ablumunits, et al., 1998, J Autoimmun. 11, 73). IFN .gamma. along with TNF, IL-2 and IL-6 lead to the activation of most peripheral T-cells prior to the development of lesions in the central nervous system for diseases such as multiple sclerosis (MS) and AIDS dementia complex (Martino et al., 1998, Ann Neurol. 43, 340). Atherosclerotic lesions result in arterial disease that can lead to cardiac and cerebral infarction. Many activated immune cells are present in these lesions, mainly T-cells and macrophages. These cells produce large amounts of proinflammatory cytokines such as TNF, IL-1 and IFN .gamma.. These cytokines are thought to be involved in promoting apoptosis or programmed cell death of the surrounding vascular smooth muscle cells resulting in the atherosclerotic lesions (Geng, 1997, Heart Vessels Suppl 12, 76). Allergic subjects produce mRNA specific for IFN .gamma. following challenge with Vespula venom (Bonay, et al., 1997, Clin Exp Immunol. 109, 342). The expression of a number of cytokines, including IFN .gamma. has been shown to increase following a delayed type hypersensitivity reaction thus indicating a role for IFN .gamma. in atopic dermatitis (Szepietowski, et al., 1997, Br J Dermatol. 137, 195). Histopathologic and immunohistologic studies were performed in cases of fatal cerebral malaria. Evidence for elevated IFN .gamma. amongst other cytokines was observed indicating a role in this disease (Udomsangpetch et al., 1997, Am J Trop Med Hyg. 57, 501). The importance of free radical species in the pathogenesis of various infectious diseases has been established. The nitric oxide synthesis pathway is activated in response to infection with certain viruses via the induction of proinflammatory cytokines such as IFN .gamma. (Akaike, et al., 1998, Proc Soc Exp Biol Med. 217, 64). Patients, chronically infected with hepatitis B virus (HBV) can develop cirrhosis and hepatocellular carcinoma. Viral gene expression and replication in HBV transgenic mice can be suppressed by a post-transcriptional mechanism mediated by IFN .gamma., TNF and IL-2 (Chisari, et al., 1995, Springer Semin Immunopathol. 17, 261). IFN .gamma. can selectively inhibit cytokine induced bone resorption. It appears to do this via the intermediacy of nitric oxide (NO) which is an important regulatory molecule in bone remodeling. NO may be involved as a mediator of bone disease for such diseases as: the rheumatoid arthritis, tumor associated osteolysis and postmenopausal osteoporosis (Evans, et al., 1996, J Bone Miner Res. 11, 300). Studies with gene deficient mice have demonstrated that the IL-12 dependent production of IFN .gamma. is critical in the control of early parasitic growth. Although this process is independent of nitric oxide the control of chronic infection does appear to be NO dependent (Alexander et al., 1997, Philos Trans R Soc Lond B Biol Sci 352, 1355). NO is an important vasodilator and convincing evidence exists for its role in cardiovascular shock (Kilboum, et al., 1997, Dis Mon. 43, 277). IFN .gamma. is required for progression of chronic intestinal inflammation in such diseases as Crohn's disease and inflammatory bowel disease (IBD) presumably through the intermediacy of CD4+lymphocytes probably of the TH1 phenotype (Sartor 1996, Aliment Pharmacol Ther. 10 Suppl 2, 43). An elevated level of serum IgE is associated with various atopic diseases such as bronchial asthma and atopic dermatitis. The level of IFN .gamma. was negatively correlated with serum IgE suggesting a role for IFN .gamma. in atopic patients (Teramoto et al., 1998, Clin Exp Allergy 28, 74).

WO 01/01986 discloses particular compounds alleged to having the ability to inhibit TNF-alpha. The specific inhibitors disclosed are structurally distinct from the novel compounds disclosed in the present application disclosed hereinbelow. Certain compounds disclosed in WO 01/01986 are indicated to be effective in treating the following diseases: dementia associated with HIV infection, glaucoma, optic-neuropathy, optic neuritis, retinal ischemia, laser induced optic damage, surgery or trauma-induced proliferative vitreoretinopathy, cerebral ischemia, hypoxia-ischemia, hypoglycemia, domoic acid poisoning, anoxia, carbon monoxide or manganese or cyanide poisoning, Huntington's disease, Alzheimer's disease, Parkinson's disease, meningitis, multiple sclerosis and other demyelinating diseases, amyotrophic lateral sclerosis, head and spinal cord trauma, seizures, convulsions, olivopontocerebellar atrophy, neuropathic pain syndromes, diabetic neuropathy, HIV-related neuropathy, MERRF and MELAS syndromes, Leber's disease, Wemicke's encephalophathy, Rett syndrome, homocysteinuria, hyperprolinemia, hyperhomocysteinemia, nonketotic hyperglycinemia, hydroxybutyric aminoaciduria, sulfite oxidase deficiency, combined